Key result
Rare KCND3 C-terminal variants show ~8-fold enrichment in Brugada syndrome via Ito gain of function.
Why the study?
Although recent genome-wide association studies implicated KCND3 in Brugada Syndrome, the role of rare variation in this gene remained uncertain and clinically unactionable.
Are rare gain-of-function variants in KCND3 enriched in patients with Brugada Syndrome compared to controls, and do they alter Kv4.3 channel current properties and interact with common genetic variation?
Case-Control (n=3,310)
Yes
Are rare gain-of-function variants in KCND3 enriched in patients with Brugada Syndrome compared to controls, and do they alter Kv4.3 channel current properties and interact with common genetic variation?
Rare gain-of-function variants in the C-terminus of KCND3 are significantly enriched in Brugada Syndrome patients and may interact epistatically with common regulatory variants to modulate disease penetrance, Challenging the previous ClinGen classification of KCND3 as having a disputed association.
May support KCND3 sequencing in Brugada syndrome evaluation; extends GWAS evidence for Ito but leaves clinical adoption open.
Background Dysfunction of the KCND3 -encoded K v 4.3 channel, which carries the transient outward potassium current ( I to ), has long been suspected to contribute to the pathophysiology of Brugada Syndrome (BrS). Although recent genome-wide association studies (GWAS) have implicated KCND3 , the role of rare variation in this gene remains uncertain and clinically unactionable. Methods Genome sequencing was performed in 983 BrS probands from Europe and Thailand. Putative gain-of-function (GoF) rare variants in KCND3 identified in patients were functionally characterized by patch-clamp analysis of K v 4.3 current properties using a HEK293 cell heterozygous model. Biobank datasets were utilized to evaluate rare-common variant interaction at the KCND3 locus. Results Eight BrS cases carried six different rare KCND3 variants which clustered at the K v 4.3 C-terminus, with terminal exon rare variants significantly enriched in cases versus study (p=0.004) and population (p=2.0e −6 ) controls. Four of the five KCND3 case variants studied demonstrated significant GoF effects versus wild-type and putative benign variants, including increased I to amplitude (p.Leu586Val, p.Ala634Thr) and slower inactivation (p.Gly600Arg, p.Ala654Thr, p.Ala634Thr). Analysis of p.Gly600Arg carriers in the UK Biobank and All of Us revealed a significant enrichment of the protective KCND3 expression-reducing allele of the GWAS lead single-nucleotide polymorphism rs12090194, suggesting a possible epistatic common-rare variant interaction modifies penetrance in carriers. Conclusions GoF rare variants at the C-terminus of KCND3 are associated with BrS in a small proportion of cases. Determination of the rare and common variant status in BrS patients and their relatives may provide information about disease risk.
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Liu et al. (2026) conducted a case-control in Brugada Syndrome (n=3,310). Rare gain-of-function variants in the terminal exon (C-terminus) of KCND3 vs. Ancestry-matched study controls and population controls was evaluated on Enrichment of rare missense variants in the terminal exon (C-terminus) of KCND3 (8-fold enrichment, p=0.004). Rare C-terminal KCND3 variants showed an 8-fold enrichment in Brugada Syndrome cases compared to study controls (p=0.004) and population controls (p=2.0e-6), with gain-of-function effects on Ito.
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